In diseases such as osteoarthritis and rheumatism there is destruction of the joint caused in particular by the proteolytic breakdown of collagen by collagenases. Collagenases belong to the superfamily of metalloproteinases (MP) or matrix metalloproteinases (MMP or MMPs). The MMPs form a group of Zn-dependent enzymes involved in the biodegradation of the extracellular matrix (D. Yip et al., Investigational New Drugs 1999, 17, 387-399 and Michaelides et al., Current Pharmaceutical Design 1999, 5, 787-819). These MMPs are capable in particular of breaking down fibrillary and non-fibrillary collagen, and proteoglycans, both of which represent important matrix constituents. MMPs are involved in processes of wound healing, of tumor invasion, metastasis migration and in angiogenesis, multiple sclerosis and heart failure (Michaelides et al., ibid, page 788). In particular they play an important part in the breakdown of the joint matrix in arthrosis and arthritis, whether osteoarthrosis, osteoarthritis or rheumatoid arthritis.
The activity of MMPs is moreover essential for many of the processes involved in atherosclerotic plaque formation, such as infiltration of inflammatory cells, smooth muscle cell migration, and proliferation and angiogenesis (S. J. George, Exp. Opin. Invest. Drugs 2000, 9 (5), 993-1007). Moreover, matrix degradation by MMP may cause plaque instabilities or even ruptures, possibly leading to the signs and symptoms of atherosclerosis, unstable angina pectoris, myocardial infarction or stroke (E. J. M. Creemers et al, Circulation Res. 2001, 89, 201-210). Considered overall, the entire MMP family can break down all the components of the extracellular matrix of the blood vessels; their activity is therefore subject in a high degree to regulatory mechanisms in normal blood vessels. Elevated MMP activity during plaque formation and plaque instability is caused by increased cytokine- and growth factor-stimulated gene transcription, increased zymogen activation and an imbalance in the MMP-TIMP ratio (tissue inhibitors of metalloproteases). MMP inhibition or restoration of the MMP-TIMP balance is therefore of assistance in the treatment of atherosclerotic disorders. In addition, besides atherosclerosis, other cardiovascular disorders are also at least partly caused by an elevated MMP activity, such as, for example, restenosis, dilated cardiomyopathy and the myocardial infarction which has already been mentioned. It has been possible to show in experimental animal models of these disorders that distinct improvements are achieved by administration of synthetic MMP inhibitors, e.g. relating to the formation of atherosclerotic lesions, neointima formation, left ventricular remodeling, dysfunction of pumping efficiency or healing of infarctions. Detailed tissue analysis in various preclinical studies with MMP inhibitors showed reduced collagen damage, improved extracellular matrix remodeling and an improved structure and function of myocardium and vessels. Of these processes, in particular matrix remodeling processes and MMP-regulated fibroses are regarded as important components in the progression of heart diseases (infarction) (Drugs 2001, 61, 1239-1252).
MMPs cleave matrix proteins such as collagen, laminin, proteoglycans, elastin or gelatin, and MMPs moreover process (i.e. activate or deactivate) by cleavage a large number of other proteins and enzymes under physiological conditions, so that they are important in the whole body, with particular importance in connective tissue and bone.
Substituted tetrahydroisoquinolines were described as inhibitors of MMPs for example in the patent applications WO9718194, CN1380288A, WO03016248 and DE102004031850.6, and in Bioorg. Med. Chem. Lett. 2004, 14, 47-50 and Current Medicinal Chemistry 2001, 8, 425-474.
The compounds of the present invention are usually distinguished by an improved solubility and by a lower tendency to bind to plasma proteins and a greater activity, especially in serum-based assay systems. The improved properties were achieved according to the invention through incorporation of at least one solubility-increasing group X-Q-Y which reduces the lipophilicity of the compounds of the invention.